Inner ear defects and hearing loss in mice lacking the collagen receptor DDR1.

Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor that is activated by native collagen. The physiological functions of DDR1 include matrix homeostasis and cell growth, adhesion, branching, and migration, but the specific role of DDR1 in the development and function of the inner ear has not been analyzed. Here, we show that deletion of the DDR1 gene in mouse is associated with a severe decrease in auditory function and substantial structural alterations in the inner ear. Immunohistochemical analysis demonstrated DDR1 expression in several locations in the cochlea, mostly associated with basement membrane and fibrillar collagens; in particular in basal cells of the stria vascularis, type III fibrocytes, and cells lining the basilar membrane of the organ of Corti. In the stria vascularis, loss of DDR1 function resulted in altered morphology of the basal cells and accumulation of electron-dense matrix within the strial epithelial layer in conjunction with a focal and progressive deterioration of strial cells. Cell types in proximity to the basilar membrane, such as Claudius', inner and outer sulcus cells, also showed marked ultrastructural alterations. Changes in the organ of Corti, such as deterioration of the supporting cells, specifically the outer hair cells, Deiters', Hensen's and bordering cells, are likely to interfere with mechanical properties of the organ and may be responsible for the hearing loss observed in DDR1-null mice. These findings may also have relevance to the role of DDR1 in other disease processes, for example, those affecting the kidney.